Captopril treatment during development alleviates mechanically induced aortic remodeling in newborn elastin knockout mice

Abstract

Deposition of elastin and collagen in the aorta correlate with increases in blood pressure and flow during development, suggesting that the aorta adjusts its mechanical properties in response to hemodynamic stresses. Elastin knockout ( Eln ^−/− ) mice have high blood pressure, pathological remodeling of the aorta, and die soon after birth. We hypothesized that decreasing blood pressure in Eln ^−/− mice during development may reduce hemodynamic stresses and alleviate pathological remodeling of the aorta. We treated Eln ^+/+ and Eln ^−/− mice with the anti-hypertensive medication captopril throughout embryonic development and then evaluated left ventricular (LV) pressure and aortic remodeling at birth. We found that captopril treatment decreased Eln ^−/− LV pressure to values near Eln ^+/+ mice and alleviated the wall thickening and changes in mechanical behavior observed in untreated Eln ^−/− aorta. The changes in thickness and mechanical behavior in captopril-treated Eln ^−/− aorta were not due to alterations in measured elastin or collagen amounts, but may have been caused by alterations in smooth muscle cell (SMC) properties. We used a constitutive model to understand how changes in stress contributions of each wall component could explain the observed changes in composite mechanical behavior. Our modeling results show that alterations in the collagen natural configuration and SMC properties in the absence of elastin may explain untreated Eln ^−/− aortic behavior and that partial rescue of the SMC properties may account for captopril-treated Eln ^−/− aortic behavior.